Melatonin (N-acetyl-5-methoxytryptamine), formula (I),
is a neurohormone produced primarily by the pineal gland, and to a lesser extent by extra pineal tissues such as the retina, harderian gland, and gastrointestinal tract. The synthesis of melatonin is regulated by circadian and seasonal variations in day length through a polysynaptic neuronal pathway from the retina to the pineal gland. Studies indicate that melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight, and metabolism in photopeliodic mammals, as well as the control of circadian rhythms and the modulation of retinal physiology. Melatonin has been detected in numerous central and peripheral tissues using the specific radioligand 2-[125I]iodomelatonin described in Delagrange et al., Clin. Neuropharinacol., 20, 482 (1997). Many of the effects of melatonin are mediated through high affinity G-protein-coupled receptors expressed primarily in the brain, retina, pituitary, and blood vessels (see, e.g., Mahle et al., J. Biol. Rhymthms, 12, 690 (1997)).
The search for novel high-affinity melatonin ligands has led to the synthesis of numerous indole and non-indole melatonin derivatives, and the elucidation of a structure-activity relationship for melatonin binding affinity (see, e.g., Methe-Allainmat et al., Expert Opin. Ther. Pat., 7, 1447 (1997), and Mor et al., Curr. Med. Chem., 6, 501-518(1999)). The melatonin derivatives were reported to be useful for treating desynchronization disorders (see, e.g., U.S. Pat. No. 6,180,657), and mammalian breast carcinoma in combination with antiestrogen compounds (see, e.g., U.S. Pat. No. 5,196,435). Melatonin derivatives also have been used as an antioxidant (see, e.g., U.S. Pat. No. 6,436,984), as well as a general anesthetic (see, e.g., U.S. Pat. No. 6,552,064). A general anesthetic is one which causes a patient to lose consciousness. This type of agent often is referred to as a “hypnotic” agent.
Low-level dosing of oral melatonin in a sublingual fashion has been shown to be effective for pre-medication prior to administering a general anesthetic (see, e.g., British Journal of Anesthesia, 82(6), 875-80 (1999)). In addition, U.S. Pat. No. 6,552,064 discloses the use of melatonin as a general anesthetic. Experiments disclosed therein demonstrate the effectiveness of melatonin for induction of general anesthesia in rats in comparison to other known anesthetics. Cumulative intravenous (iv) injection of divided doses of melatonin caused a progressive loss of righting reflex, grip strength, and eyelash reflex. The ED95 (95% CI, for loss of righting reflex) of melatonin is 312 mg/mL, as compared to 8 mg/kg for thiopental, and 14.9 mg/kg for propofol. Bolus injection of 312 mg/mL of melatonin, or 10 mg/kg of propofol, caused an immediate loss of righting reflex.
There remains a need for new melatonin derivatives, and methods for using such derivatives to induce general anesthesia, hypnosis, or sleep in a subject. The invention provides such derivatives and methods. The inventive derivatives are more effective as an anesthetic than melatonin alone. Thus, the derivatives of the invention can be used in larger doses for general anesthesia, and in smaller doses for hypnosis, sedation, and sleep induction. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.